Immune checkpoint inhibitor-related hepatotoxicity: A review

Table 1 Incidence of severe hepatotoxicity by immunotherapy agent used as reported in key phase II and III clinical trials

Class	Agent	Ref.	Indication	Incidence of hepatoxicity (all grades) % (no. of patients)	Incidence of ≥ grade 3 hepatoxicity % (no. of patients)
CTLA-4	Ipilimumab (standard dose) 3 mg/kg	Hodi et al[71], 2018	Melanoma	0.3 (1/311)	0 (0/311)
		Weber et al[72], 2009	Melanoma	15.5 (9/58)	10.3 (6/58)
		Hodi et al[2], 2010	Melanoma	3.8 (5/131)	0 (0/131)
			Melanoma	2.1 (8/380) Ipilimumab with gp100	1.1 (4/380) pilimumab with gp100
		Wolchok et al[73], 2010	Melanoma	26.4% (19/72)	0 (0/72)
		Robert et al[74], 2011	Melanoma	29.1 (72/247)	20.6 (51/247)
	Ipilimumab (high dose) 10 mg/kg	Wolchok et al[73], 2010	Melanoma	70.4 (50/71)	15.5 (11/71)
	Tremelimumab	Ribas et al[75], 2013	Melanoma	0.6 (2/325)	0.6 (2/325)
Anti-PD-1	Nivolumab	Hodi et al[71], 2018	Melanoma	0.3 (1/313)	0.3 (1/313)
		Weber et al[76], 2017	Melanoma	1.9 (11/576)	0.7 (4/576)
		Brahmer et al[77], 2015	Squamous cell NSCLC	1.5 (2/131)	0 (0/131)
		Borghaei et al[78], 2015	Non-squamous NSCLC	3.1 (9/287)	0 (0/287)
		Robert et al[79], 2014	Melanoma	1.1 (1/89)	1.1 (1/89)
	Pembrolizumab	Robert et al[79], 2014	Melanoma	0 (0/84)	0 (0/84)
		Eggermont et al[80], 2018	Melanoma	1.8 (9/509)	1.4 (7/509)
	Cemiplimab	Migden et al[81], 2018	Cutaneous Squamous-Cell Carcinoma	8.5 (5/59)	0 (0/59)
Anti-PD-L1	Atezolizumab	Jotte et al[82], 2020	Squamous NSCLC	17.4 (58/334)	5.4 (18/334)
	Atezolizumab + Bevacizumab (anti-VEGF antibody)	Finn et al[3], 2020	HCC	33.4 (110/329)	10.6 (35/329)
	Avelumab	D’Angelo et al[83], 2020	Metastatic Merkel cell carcinoma	1.1 (1/88)	1.1 (1/88)
	Durvalumab	Garassino et al[84], 2018	Advanced NSCLC	0.2 (1/444)	0.2 (1/444)
Combination Therapy	Ipilimumab + Nivolumab	Hodi et al[71], 2018	Melanoma	3.2 (10/313)	2.6 (8/313)
		Postow et al[85], 2015	Melanoma	22.3 (21/94)	10.6 (10/94)
		Larkin et al[86], 2015	Melanoma	17.6 (55/313)	8.3 (26/313)
		Wolchok et al[73], 2010	Melanoma	20.8 (11/53)	11.3 (6/53)

Grading of severity is according to common terminology criteria for adverse events. CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; HCC: Hepatocellular carcinoma; no. of: Number of; NSCLC: Non-small cell lung cancer; PD-1: Programmed cell death protein 1; PD-L1: Programmed death-ligand 1; VEGF: Vascular endothelial growth factor.

Table 2 Differential diagnosis and suggested investigations

System	Differential diagnosis	Investigations
Drug-induced liver injury	(1) Other co-administered anti-cancer drugs; (2) Alcohol related liver disease; and (3) Acetaminophen toxicity	Medication history
Tumor-related	Metastatic disease	Abdominal imaging with ultrasound, CT or MRCP
Infectious	(1) Sepsis; (2) Acute HAV infection; (3) Acute HBV or flare of chronic HBV; (4) Chronic HCV; (5) Acute HEV; (6) Acute CMV or reactivation; and (7) Acute EBV	(1) Septic screen as appropriate; (2) Anti-HAV (IgM); (3) HBsAg, Anti-HBc IgG, IgM, ± HBV DNA; (4) Anti-HCV ± HCV RNA; (5) Anti-HEV (IgM); (6) CMV IgM and IgG ± CMV DNA; and (7) EBV IgM and IgG
Biliary disease	(1) Cholecystitis; (2) Cholangitis; and (3) Pancreatitis	(1) Abdominal imaging; and (2) Serum lipase
Autoimmune	Autoimmune hepatitis1	ANA, Anti-SMA, Anti-LKM1, serum IgG levels
Musculoskeletal	(1) Myositis (potentially an irAEs); and (2) Rhabdomyolysis	Serum CK
Metabolic	Underlying NASH	(1) Metabolic risk factors; and (2) Abdominal imaging for hepatic steatosis
Vascular	(1) Portal-vein/hepatic vein thrombosis; and (2) Ischemic hepatitis	Abdominal imaging and clinical history

¹Although anti-nuclear antibodies is frequently positive at low-titres in IC (< 1:80), specific auto-antibodies seen in autoimmune hepatitis are usually negative.

ANA: Anti-nuclear antibodies; Anti-HBc: Anti-Hepatitis B core antibody; anti-LKM1: Anti-liver-kidney microsomal 1 antibody; Anti-SMA: Anti-smooth muscle antibody; CK: Creatine kinase; CMV: Cytomegalovirus; CT: Computed tomography; EBV: Epstein-Barr virus; HAV: Hepatitis A virus; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HEV: Hepatitis E virus; irAEs: Immune-related adverse events; MRCP: Magnetic resonance cholangiopancreatography; NASH: Non-alcoholic steatohepatitis.

Table 3 Comparison of common grading systems for inhibitor-related hepatotoxicity

	Grade
	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
CTCAE[87]	(1) Asymptomatic; (2) AST or ALT > 1-3 × more than ULN; and (3) T. Bil > 1-1.5 × more than ULN	(1) Asymptomatic; (2) AST or ALT > 3-5 × more than ULN; and (3) T. Bil > 1.5-3 × more than ULN	(1) Symptomatic liver dysfunction; (2) Fibrosis on biopsy; (3) Compensated cirrhosis; (4) Reactivation of chronic hepatitis; (5) AST or ALT > 5-20 × more than ULN; and (6) T. Bil > 3-10 × more than ULN	(1) Decompensated liver function (e.g., ascites, coagulopathy, encephalopathy, coma); (2) AST or ALT > 20 × more than ULN; and (3) T. Bil > 10 × more than ULN	Death due to hepatotoxicity
DILIN[73]	(1) Elevations in serum ALT and/or ALP levels; (2) T. Bil < 2.5 ULN; (3) INR < 1.5; and (4) Present with or without symptoms (fatigue, asthenia, nausea, anorexia, RUQ pain, jaundice, pruritus, rashes, or weight loss)	(1) Elevated serum ALT and/or ALP; (2) T. Bil ≥ 2.5 ULN or INR ≥ 1.5; and (3) Symptoms may become aggravated	(1) Elevated serum ALT and/or ALP; (2) T. Bil ≥ 5 ULN ± INR ≥ 1.5; (3) Symptoms are further aggravated; (4) Indication for hospitalization; and (5) No evidence of hepatic encephalopathy	(1) Coagulation abnormality indicated by INR ≥ 1.5; (2) Signs of hepatic encephalopathy; (3) T. Bil ≥ 10 ULN or daily elevation ≥ 1.0 mg/dL in 26 wk after the DILI onset; and (4) Ascites and DILI-related dysfunction of another organ	(1) Death due to DILI; and (2) Or need to receive liver transplantation for survival

ALT: Alanine Aminotransferase; AST: Aspartate aminotransferase; CTCAE: Common terminology criteria for adverse events; DILI: Drug induced liver injury; DILIN: Drug-induced Liver Injury Network; ICH: Immune checkpoint inhibitor-induced hepatoxicity; INR: International normalized ratio; RUQ: Right upper quadrant; T. Bil: Total bilirubin; ULN: Upper limit of normal.

Table 4 Comparison of management recommendations for inhibitor-related hepatotoxicity by major expert societies

Grade	FDA[88]	Society of Immunotherapy of Cancer[89]	American Society of Clinical Oncology[90]	European Society for Medical Oncology[91]	Australian (eVIQ Guidelines)[53]	European Association for the Study of Liver[52]
Grade 1	(1) Monitor closely; (2) Continue ICI; and (3) Investigate for other causes of hepatitis	(1) Monitor closely; (2) Continue ICI; and (3) Investigate for other causes of hepatitis	(1) Monitor closely; (2) Continue ICI; (3) Check LFTs twice a week; and (4) Investigate for other causes of hepatitis	(1) Monitor closely; (2) Continue ICI; (3) Check LFTs weekly; and (4) Investigate for other causes of hepatitis	(1) Continue ICI; (2) Monitor LFTs more closely; and (3) Investigate for other causes of hepatitis	If irAEs are excluded (unlikely or unrelated) continue therapy with close follow-up. Start symptomatic treatment
Grade 2	(1) Withhold ICI; (2) Investigate for other causes of hepatitis; (3) Start 0.5–1.0 mg/kg/d of prednisone Po until LFTs improve to < Grade 1 then wean steroids; and (4) Consider restarting when on less than equivalent of prednisone 7.5 mg/d	(1) Withhold ICI; (2) Investigate for other causes of hepatitis; (3) Start prednisone 0.5–1 mg/kg/d Po (or equivalent) with a 4-wk taper; (4) Monitor LFTs twice a week; (5) Liver biopsy optional; and (6) Resume ICI when steroids tapered to 10 mg/d and liver enzymes are grade 1 level or better	(1) Withhold ICI; (2) Investigate for other causes of hepatitis; (3) Monitor LFTs every 3 d and if no improvement start prednisone 0.5–1 mg/kg/d Po (or equivalent); and (4) Resume ICI when LFTs grade 1 level while on less than prednisolone 10 mg/d (taper over a month)	(1) Withhold ICI; (2) Investigate for other causes of hepatitis; (3) Recheck LFTs/INR every 3 d; (4) If LFTs increase on subsequent check after stopping checkpoint inhibitor, start oral prednisolone 1 mg/kg/d; (5) Once LFTs return to grade 1, start weaning steroids; and (6) Resume ICI when liver enzymes are grade 1 level or better while on less than prednisolone 10 mg/d	(1) Withhold ICI; (2) Monitor LFTs every 3 d; (3) Investigate for other causes of hepatitis; (4) Consider corticosteroid therapy for patients who are symptomatic or worsening LFTs; and (5) Resume ICI treatment once corticosteroid treatment is complete and tapered over 4 wk	(1) Skip dose and monitor liver parameters, INR and albumin twice weekly; (2) Start symptomatic treatment; (3) If abnormal liver parameters persist longer than 2 wk, start immunosuppression and discontinue the drug; and (4) Upon improvement immunotherapy could be resumed after corticosteroid tapering
Grade 3	(1) Permanently cease ICI; (2) Start prednisone at 1–2 mg/kg/d Po (or equivalent); (3) Consider imaging and liver biopsy while assessing for alternative causes of hepatitis	(1) Permanently cease ICI; (2) Monitor complete metabolic panel every 1–2 d; (3) Start prednisone at 1–2 mg/kg/d (or equivalent); (4) If refractory to steroids, consider adding MMF. Once LFTs improve, taper over 4 wk; and (5) Consider liver biopsy	(1) Permanently discontinue medication; (2) Consider hospitalization and start IV 1–2 mg/kg/d methylprednisolone; (3) If no improvement in 3 d consider adding secondary agent; (4) Monitor LFTs daily/every other day; (5) Once LFTs improve will need to wean steroids over 4–6 wk; and (6) Do not offer infliximab	(1) Withhold ICI; (2) Investigate for other causes of hepatitis; (3) Recheck LFTs/INR daily; (4) Consider hospitalization; (5) Start prednisolone 1 mg/kg/d Po if ALT/AST < 400 U/L and normal bilirubin/albumin/INR OR start IV methylprednisolone 2 mg/kg/d if ALT/AST > 400 U/L or elevated bilirubin/INR or decreased albumin; (6) Once LFTs improve to grade 2, can switch to PO steroids and wean over 4 wk; (7) Consider rechallenge at discretion of consultant; (8) If no improvement on steroids, consider adding mycophenolate and/or tacrolimus; and (9) Do not offer infliximab	(1) Permanently discontinue treatment; (2) Investigate for other causes of hepatitis; (3) Consider liver biopsy; (4) Hospitalize patient if unwell; (5) Urgent administration of start IV 1–2 mg/kg/d methylprednisoloneFor 3 d, following high dose oral prednisolone; and (6) If no improvement on steroids, urgent referral to a gastroenterologist to prescribe other steroid-sparing agents	(1) Discontinue immunotherapy and monitor liver parameters. Consider permanent discontinuation of immunotherapy; (2) Start corticosteroids (methylprednisolone or equivalent) at a dose of 1–2 mg/kg/d depending on severity; (3) If there is no response to corticosteroids within 2–3 d, MMF should be added at 1000 mg twice daily; (4) Further immunosuppression: MMF, cyclosporine, tacrolimus, anti-thymocyte antibodies; and (5) Infliximab is not recommended
Grade 4	(1) Permanently cease ICI; (2) Start prednisone at 1–2 mg/kg/d Po (or equivalent); and (3) Consider imaging and liver biopsy while assessing for alternative causes of hepatitis	(1) Permanently cease ICI; (2) Start prednisone at 1–2 mg/kg/d Po (or equivalent); (3) Monitor complete metabolic panel every 1–2 d; (4) If refractory to steroids, consider adding MMF. LFTs improve, taper over 4 wk; and (5) Consider liver biopsy	(1) Permanently discontinue medication; (2) Consider hospitalization and start IV 2 mg/kg/d methylprednisolone; (3) Add MMF if no improvement in 72 h; (4) Consider transfer to tertiary center with hepatology consultation if no improvement; (5) Do not offer infliximab; and (6) If LFTs improve, will need steroid wean over 4–6 wk	(1) Permanently discontinue medication; (2) Consider hospitalization and start IV methylprednisolone 2 mg/kg/d; (3) Formal hepatology consultation; (4) Consider liver biopsy; (5) If no improvement on IV steroids, add MMF and/or tacrolimus; (6) Do not offer infliximab; and (7) Once LFTs improve to > grade 2, can switch to oral steroids and wean over 4 wk	(1) Permanently discontinue treatment; (2) Investigate for other causes of hepatitis; (3) Consider liver biopsy; (4) Hospitalize patient if unwell; (5) Urgent administration of start IV 1–2 mg/kg/d Methylprednisolone. For 3 d, following high dose oral prednisolone; and (6) If no improvement on steroids, urgent referral to a gastroenterologist to prescribe other steroid-sparing agents

Grading of severity is according to ommon terminology criteria for adverse events. ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; FDA: United States Food and Drug Administration; ICI: Immune checkpoint inhibitor; INR: International normalized ratio; irAEs: Immune-related adverse events; IV: Intravenous; LFTs: Liver function tests; MMF: Mycophenolate mofetil; PO: Per oral.